Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88
Cecile M. Fremond, … , Valerie F. Quesniaux, Bernhard Ryffel
Cecile M. Fremond, … , Valerie F. Quesniaux, Bernhard Ryffel
Published December 15, 2004
Citation Information: J Clin Invest. 2004;114(12):1790-1799. https://doi.org/10.1172/JCI21027.
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Article Immunology

Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88

Abstract

Toll-like receptors (TLRs) such as TLR2 and TLR4 have been implicated in host response to mycobacterial infection. Here, mice deficient in the TLR adaptor molecule myeloid differentiation factor 88 (MyD88) were infected with Mycobacterium tuberculosis (MTB). While primary MyD88–/– macrophages and DCs are defective in TNF, IL-12, and NO production in response to mycobacterial stimulation, the upregulation of costimulatory molecules CD40 and CD86 is unaffected. Aerogenic infection of MyD88–/– mice with MTB is lethal within 4 weeks with 2 log10 higher CFU in the lung; high pulmonary levels of cytokines and chemokines; and acute, necrotic pneumonia, despite a normal T cell response with IFN-γ production to mycobacterial antigens upon ex vivo restimulation. Vaccination with Mycobacterium bovis bacillus Calmette-Guérin conferred a substantial protection in MyD88–/– mice from acute MTB infection. These data demonstrate that MyD88 signaling is dispensable to raise an acquired immune response to MTB. Nonetheless, this acquired immune response is not sufficient to compensate for the profound innate immune defect and the inability of MyD88–/– mice to control MTB infection.

Authors

Cecile M. Fremond, Vladimir Yeremeev, Delphine M. Nicolle, Muazzam Jacobs, Valerie F. Quesniaux, Bernhard Ryffel

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MyD88–/– mice are unable to control an MTB infection. MyD88–/– (open cir...
MyD88–/– mice are unable to control an MTB infection. MyD88–/– (open circles), TNF–/– (open squares), and wild-type (filled squares) mice were exposed to a low aerogenic dose of MTB H37Rv (200 CFU per mouse i.n.) and monitored for body weight (A; mean values of n = 6–8 mice per group from 1 representative experiment out of 7 independent experiments) and survival (B; n = 13–24 mice pooled from several experiments; P – 0.01 between MyD88–/– or TNF–/– mice and wild-type controls, and between TNF- and MyD88-deficient mice). (C) Lung wet weight of TNF–/– mice (gray bars), MyD88–/– mice (white bars), and wild-type controls (black bars) were measured 17 and 27 days after infection. The numbers of viable bacteria present in the lungs (D) and spleen (E) of MyD88–/– (white bars) and wild-type (black bars) mice were determined after 27 days of infection (mean ± SD of n = 3–4 lung or n = 5–7 spleen samples from 1 representative experiment out of 2 or 3 independent experiments, respectively; **P – 0.01).